Generation and functional characterization of a BCL10 inhibitory peptide that represses NF-kappaB activation.

The molecular complex containing BCL10 and CARMA proteins has been recently identified as key component in the signalling transduction pathways that regulate activation of NF-kappaB transcription factor in lymphoid and non-lymphoid cells. Assembly of the molecular complexes containing BCL10 and CARMA proteins relies on homophylic interactions established between the CARD domains of these proteins. In order to identify BCL10 inhibitory peptides, we have established a method of assaying peptides derived from the CARD of BCL10 in a binding competition assays of CARD-CARD self-association. By this procedure, a short peptide corresponding to the amino acidic residues 91-98 of BCL10 has been selected as an effective inhibitor of the protein self-association. When tested in cell assays for its capacity to block NF-kappaB activation, this peptide represses activation of NF-kappaB mediated by BCL10, CARMA3 and PMA/ionomycin stimulation. Collectively, these results indicate that the region 91-98 of BCL10 is involved in BCL10 self-association and also participates in the interaction with external partners. Furthermore, we prove that blocking BCL10 auto-association may potentially be used for the treatment of pathologic conditions associated with inappropriate NF-kappaB activation.